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Comprehensive Publication Review:

Comprehensive Publication Review:. Dyslipidemia, Chronic Kidney Disease and Cardiovascular Disease. Table of Contents. Author(s) Publication Slides Attman P-O, et al Curr Opin Lipidol 2009 3 – 14 Nogueira J, et al Clin J Am Soc Nephrol 2007 15 – 24

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Comprehensive Publication Review:

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  1. Comprehensive Publication Review: Dyslipidemia, Chronic Kidney Diseaseand Cardiovascular Disease

  2. Table of Contents Author(s) Publication Slides Attman P-O, et al Curr Opin Lipidol 2009 3 – 14 Nogueira J, et al Clin J Am Soc Nephrol 2007 15 – 24 Snyder JJ, et al Am J Nephrol 2009 25 – 32 Levin A, et al CMAJ 2008 33 – 46 Astor BC, et al Am J Epidemiol 2008 47 – 56 Matsushita K, et alClin Epidemiol 2009 57 – 64 Shepherd J, et al J Am Coll Cardiol 2008 65 – 71 Fellström B, et al N Engl J Med 2009 72 – 78 Nakamura T, et al Pharmacol Res 2009 79 – 86 Türk TR, et al Nephrol Dial Transplant 2008 87 – 95 Baigent C, et alKidney Int Suppl 2003 96 – 105

  3. Dyslipidemia of Kidney Disease Attman PO, et al: Curr Opin Lipidol 2009; 20(4):293-9.

  4. Dyslipidemia of Kidney Disease • Objective: To summarize current knowledge of the pathophysiology of renal dyslipidemia and the therapeutic options • Topics covered: • Lipoprotein profile • Causes • Consequences • Therapy Attman PO, et al: Curr Opin Lipidol 2009; 20(4):293-9.

  5. Background on Dyslipidemia in CKD • With declining renal function, a complex series of various metabolic changes and adaptations occur • In advanced chronic kidney disease (CKD), the lipid profile is characterized by the following: • Markedly elevated triglycerides and triglyceride-rich apoB-containing lipoproteins • Decreased HDL-cholesterol (HDL-C) • Minimal to no change in LDL-cholesterol (HDL-C) • This profile has been linked to high incidence of cardiovascular (CV) morbidity and mortality Adapted from Attman PO, et al: Curr Opin Lipidol 2009; 20(4):293-9.

  6. Consequences of Renal Dyslipidemia • Cardiovascular disease (CVD) is the main cause of mortality during dialysis and after renal transplantation • The accelerated development of atherosclerosis and CVD in progressive renal disease is well documented • The prevalence of CVD is also high in renal patients in the early stages of CKD, long before the time of initiating dialysis Adapted from Attman PO, et al: Curr Opin Lipidol 2009; 20(4):293-9.

  7. Lipid-lowering Therapy forRenal Dyslipidemia • Lipid-lowering intervention has the theoretical potential to attenuate deleterious processes associated with CKD: • Accelerated atherosclerosis • Progression of renal functional impairment • However, to date, only a few studies have been specifically designed to address these issues Adapted from Attman PO, et al: Curr Opin Lipidol 2009; 20(4):293-9.

  8. Post-hoc Analyses of CKD Patients in Major Statin Trials Adapted from Attman PO, et al: Curr Opin Lipidol 2009; 20(4):293-9.

  9. Prospective Studies of Lipid-lowering in Stage 4 CKD Adapted from Attman PO, et al: Curr Opin Lipidol 2009; 20(4):293-9.

  10. Why Aren't Statins Powerfully Effective in Stage 4 CKD? • Statins are not very effective in reducing triglyceride-rich apoB- and apoC-containing lipoproteins • This is the major lipoprotein abnormality of advanced renal failure • We should therefore not expect statins to significantly attenuate renal dyslipidemia in advanced CKD Adapted from Attman PO, et al: Curr Opin Lipidol 2009; 20(4):293-9.

  11. Ongoing Studies ofLipid-lowering in CKD Adapted from Attman PO, et al: Curr Opin Lipidol 2009; 20(4):293-9.

  12. Attenuation of Progression of Renal Disease? • The TNT study (patients with coronary heart disease [CHD] ± CKD) suggested that high-dose atorvastatin seemed to be beneficial, increasing eGFR by ~ 1 mL/min • Meta-analyses based on small studies have suggested a positive effect of statin treatment on the progression of CKD • However: • Post-hoc analyses of larger lipid-lowering intervention trials have failed to show benefit or have been inconclusive • Confounding effects of concomitant antihypertensive therapy cannot be ruled out • The impact of lipid-lowering therapy on progression of renal disease remains to be established Adapted from Attman PO, et al: Curr Opin Lipidol 2009; 20(4):293-9.

  13. Cardiovascularrisk reductionby statins? GFR 100 Renoprotectionby statins? 50 Risk Reduction with Statins in Renal Dyslipidemia Adapted from Attman PO, et al: Curr Opin Lipidol 2009; 20(4):293-9.

  14. Dyslipidemia of Kidney Disease: Conclusions • Recent studies have shown important pathophysiological links between an increase of apoC-III-containing lipoproteins and the inflammatory processes that ultimately can result in accelerated vascular disease in CKD patients • For stage 1–3 CKD patients, lipid-lowering interventions should be beneficial • Further research is required for definitive answers • Statin treatment cannot reduce CVD in patients with renal failure on hemodialysis Attman PO, et al: Curr Opin Lipidol 2009; 20(4):293-9.

  15. The Unique Character of CVD in CKD and Its Implications for Treatment with Lipid-lowering Drugs Nogueira J, et al: Clin J Am Soc Nephrol 2007;2(4):766-85.

  16. CVD in CKD: Implications for Lipid-lowering Treatment • Background: • There are very limited data to guide the use of lipid-lowering drugs in CKD • Data from trials in the general population may not be generalizable to those with CKD • Objectives: • To review the data that are pertinent to the CKD population • To update recommendations for use of lipid-lowering therapy in the CKD population Nogueira J, et al: Clin J Am Soc Nephrol 2007; 2(4):766-85.

  17. Evidence for Lipid-lowering Therapy in CKD: Subgroup Analyses of Major Trials Adapted from Nogueira J, et al: Clin J Am Soc Nephrol 2007; 2(4):766-85.

  18. Completed Prospective Trials of Lipid-lowering Therapy in CKD *Precursor to the larger SHARP study, currently ongoing. Adapted from Nogueira J, et al: Clin J Am Soc Nephrol 2007; 2(4):766-85.

  19. Potential Contributors to the Development of CVD in Patients with CKD HD: hemodialysis; IDL: intermediate-density lipoprotein Adapted from Nogueira J, et al: Clin J Am Soc Nephrol 2007; 2(4):766-85.

  20. Alterations in Lipid Profiles in CKD Adapted from Nogueira J, et al: Clin J Am Soc Nephrol 2007; 2(4):766-85.

  21. Updated Recommendations for Lipid-lowering Therapy in CKD • It is advisable to aggressively treat individuals who have an eGFR of 30 to 60 mL/min/1.73 m2 and have known CHD and probably those without known coronary disease • On the basis of the findings from the Pravastatin Pooling Project • It is reasonable to apply the currently accepted and footnoted guidelines (NCEP ATP-III) schema for treatment on the basis of LDL-C levels and LDL-C goals to those who have not yet reached end-stage renal disease (ESRD) Adapted from Nogueira J, et al: Clin J Am Soc Nephrol 2007; 2(4):766-85.

  22. Updated Recommendations for Lipid-lowering Therapy in CKD • Itmaybe advisable to treat those with high risk for atherosclerotic cardiac events regardless of initial LDL level to achieve a marked (at least 30 to 40%) reduction in LDL • A lower goal LDL of 70 mg/dL may be a reasonable therapeutic option in patients with CKD • The increase in mortality in hemodialysis patients at lower cholesterol levels demands caution within this population Adapted from Nogueira J, et al: Clin J Am Soc Nephrol 2007; 2(4):766-85.

  23. Updated Recommendations for Lipid-lowering Therapy in CKD • It is reasonable but not mandatory to consider a reduced GFR, proteinuria, and perhaps microalbuminuria to be a “CHD-risk equivalent” • Routine treatment of hemodialysis patients with diabetes may not be warranted • Ezetimibe is a reasonable choice for a second-line lipid-lowering therapy in the CKD population and probably in kidney transplant recipients Adapted from Nogueira J, et al: Clin J Am Soc Nephrol 2007; 2(4):766-85.

  24. CVD in CKD and Implications for Lipid-lowering Treatment: Conclusions • As the severity and duration of uremia increase, the epidemiology, pathophysiology and response to treatment of CVD changes gradually from what is experienced in the general population to what is unique to the uremic milieu • It becomes much less clear whether lipid-lowering agents are of benefit as CKD advances, especially in dialysis patients • There is great potential for benefit of statins and other lipid-lowering agents in this population, but the need for further study is urgent Nogueira J, et al: Clin J Am Soc Nephrol 2007; 2(4):766-85.

  25. KDOQI Hypertension, Dyslipidemia, and Diabetes Care Guidelines and Current Care Patterns in the United States CKD Population: National Health and Nutrition Examination Survey 1999-2004 Snyder JJ, et al: Am J Nephrol 2009; 30(1):44-54.

  26. Hypertension, Dyslipidemia and Diabetes Care in CKD • Objective:To assess current CKD population health and adherence to recommendations in the United States • Subjects:14,213 patients with CKD, aged ≥20 years • From the National Health and Nutrition Examination Survey 1999-2004 • Assessments:Rates of hypertension and dyslipidemia management and diabetes control, stratified by CKD status and prior history of CVD Snyder JJ, et al: Am J Nephrol 2009; 30(1):44-54.

  27. Background • The US National Kidney Foundation published a series of guidelines in the 2000s • Aim was to slow CKD progression and reduce morbidity and mortality • CKD patients are more than 6 times more likely to die from CVD than to reach ESRD • Understanding of adherence to guidelines for CVD risk factors is crucial to evaluating overall health of these patients Adapted from Snyder JJ, et al: Am J Nephrol 2009; 30(1):44-54.

  28. % 3% 3% 4% ATC III cholesterolclassification 100 10% 10% 9% 90 26% 24% 24% Very high, ≥190 mg/dL 80 70 High, 160-189 mg/dL 60 35% 32% 31% Borderline high, 130-159 mg/dL 50 40 Near optimal, 100-129 mg/dL 30 31% 30% 28% 20 Optimal, <100 L 10 0 None Stage 1 – 2 Stage 3 – 4 CKD stage Measured LDL-C Levels,by Stage of CKD Adapted from Snyder JJ, et al: Am J Nephrol 2009; 30(1):44-54.

  29. High Cholesterol: Prevalence, Awareness, Treatment and Control Values are %. CKD = Chronic kidney disease; LDL = low-density lipoprotein; HDL = high-density lipoprotein. 1 Taking lipid-lowering agents, dieting, or not meeting National Cholesterol Education ProgramAdult Treatment Panel III LDL cholesterol targets. 2. National Cholesterol Education Program Adult Treatment Panel III, ≥40 mg/dL. Unadjusted. 3. Unadjusted Adapted from Snyder JJ, et al: Am J Nephrol 2009; 30(1):44-54.

  30. Odds Ratios for Control of High Cholesterol by CKD Stage: No History of CVD Reference:non-CKD = 1 CKDstage OR 1 – 2 1.25 Highcholesterol* 3 – 4 5.03 1 – 2 0.89 Awareness* 3 – 4 0.35 1 – 2 0.89 Treatment* 3 – 4 0.39 1 – 2 0.75 Control* 3 – 4 0.14 1 – 2 0.90 LLA use 3 – 4 0.84 5.0 0.2 0.6 1.4 2.6 Odds ratio (log scale) *Significant interaction between history of CVD and CKD stage Adapted from Snyder JJ, et al: Am J Nephrol 2009; 30(1):44-54.

  31. Odds Ratios for Control of High Cholesterolby CKD Stage: History of CVD Reference:non-CKD = 1 CKDstage OR 1 – 2 0.41 High cholesterol* 0.39 3 – 4 1 – 2 0.75 Awareness* 0.85 3 – 4 1 – 2 0.75 Treatment* 1.02 3 – 4 1 – 2 1.28 Control* 1.69 3 – 4 1 – 2 0.90 LLA use 0.84 3 – 4 5.0 0.2 0.6 1.4 2.6 Odds ratio (log scale) *Significant interaction between history of CVD and CKD stage Adapted from Snyder JJ, et al: Am J Nephrol 2009; 30(1):44-54.

  32. Dyslipidemia in CKD: Conclusions • The U.S. National Kidney Foundation has identified many target areas for preventative care in the CKD population • Identifying risk factors such as dyslipidemia could improve morbidity and mortality • In later stage CKD, those with reported CVD history were more likely to be aware of, treated for, and in control of high cholesterol than those without CVD • Participants with CKD stages 1–2 were less likely to have controlled cholesterol if they had reported CVD history • This represents a care gap for earlier-stage patients • Further research is warranted to investigate these differences • There are many opportunities for improvement in the management of patients with CKD Snyder JJ, et al: Am J Nephrol 2009; 30(1):44-54.

  33. Guidelines for the Management of CKD Levin A, et al: CMAJ 2008; 179(11):1154-62.

  34. Review of Canadian Guidelines for the Management of CKD • Objective: To outline evidence-based recommendations from the Canadian Society of Nephrology guidelines on aspects of management of CKD • Topics covered: • Targets for various abnormalities • Strategies for treatment • Frequency of follow-up • Focus:For the purposes of this document, the focus is on CV abnormalities, specifically dyslipidemia Levin A, et al: CMAJ 2008; 179(11):1154-62.

  35. A Few Notes About the Canadian Guidelines for the Management of CKD • The recommendations are meant for pre-dialysis patients only • The target audience includes both general practitioners and specialists • The guidelines are part of a comprehensive national strategy management • The recommendations are aligned with guidelines of other national societies (e.g., Canadian Diabetes Association, Canadian Hypertension Education Program and Canadian Cardiovascular Society) Adapted from Levin A, et al: CMAJ 2008; 179(11):1154-62.

  36. Definition of CKD • The presence of kidney damage for a period greater than 3 months • Abnormal kidney function is noted if: • Estimated / measured GFR <60 mL/min/1.73 m2 • Estimated / measured GFR >60 mL/min/1.73 m2,accompanied by: • Abnormalities of urine sediment; or • Abnormal results of imaging tests; or • If the patient has had a kidney biopsy with documented abnormalities Adapted from Levin A, et al: CMAJ 2008; 179(11):1154-62.

  37. CKD and CVD • CKD is estimated to affect between 1.9 million and 2.3 million Canadians • This is a major public health problem • CKD often coexists with CVD and diabetes • CKD is recognized as a risk factor for all-cause mortality and CVD • Most patients with CKD will die of events related to CVD before ESRD develops • An important focus of care for patients with CKD includes management of CVD risk factors Adapted from Levin A, et al: CMAJ 2008; 179(11):1154-62.

  38. Stages of CKD* * Kidney damage or GFR less than 60 mL/min/1.73 m2 for 3 or more months. † Pathologic abnormalities or markers of damage, including persistent proteinuria, abnormalities in urine sediment (persistent presence of erythrocytes, erythrocyte casts, leukocytes or leukocyte casts) or abnormal results in imaging studies (evidence of scarring or small kidneys on ultrasound or bilateral cystic changes consistent with polycystic kidney disease) Adapted from Levin A, et al: CMAJ 2008; 179(11):1154-62.

  39. Canadian CKD Guidelines:Shared Care Is Recommended • The guidelines were developed to facilitate shared care of patients with CKD by GPs and specialists (including internists, endocrinologists, cardiologists and nephrologists) • Most cases of nonprogressive CKD can be managed in primary care without referral to a nephrologist Adapted from Levin A, et al: CMAJ 2008; 179(11):1154-62.

  40. Scenarios in Which Referral to a Nephrologist Should Be Considered • Acute kidney failure • Persistent eGFR <30 mL/min/1.73 m2 • Progressive decline of kidney function • Ratio of urine protein to creatinine >100 mg/mmol (about 900 mg/24 h) • Urine albumin to creatinine ratio >60 mg/mmol (about 500 mg/24 h) • Inability to achieve treatment targets • Rapid changes in kidney function Adapted from Levin A, et al: CMAJ 2008; 179(11):1154-62.

  41. Recommendations for Screening for Dyslipidemia in CKD • A fasting lipid profile (total cholesterol, LDL-C, HDL-C and triglyceride) should be measured in adults with stage 1–3 CKD • A fasting lipid profile should be measured in adults with stage 4 CKD only if the results would influence the decision to initiate or alter lipid-modifying treatment Adapted from Levin A, et al: CMAJ 2008; 179(11):1154-62.

  42. Canadian CKD Guidelines: Recognition of Common Comorbidities and Risk Factors • Groups at particular risk of developing CKD: • CVD • Diabetes • Specific ethnicities • Family history of CKD • There is a high prevalence of dyslipidemia at every stage of CKD Adapted from Levin A, et al: CMAJ 2008; 179(11):1154-62.

  43. Recommendations for Monitoring Dyslipidemia in CKD • Lipid profiles should be measured after an overnight fast (ideally ≥12 h duration) • Total cholesterol, LDL-C, HDL-C and triglycerides should be measured • Fasting lipid profiles should be measured no sooner than 6 weeks after initiation or change in pharmacologic therapy • Thereafter, lipid profiles should be monitored every 6–12 months if the results could influence subsequent therapeutic decisions Adapted from Levin A, et al: CMAJ 2008; 179(11):1154-62.

  44. Recommendations forLDL Lowering in CKD Adapted from Levin A, et al: CMAJ 2008; 179(11):1154-62.

  45. Recommendations for Monitoring for Adverse Effects of Medication • Serial monitoring of creatinine kinase and alanine aminotransferase: • Not required for asymptomatic patients with CKD taking a low to moderate dose of statin (≤20 mg/d of simvastatin or atorvastatin, or an equivalent dose of another statin) • Should be measured every 3 months for patients with stage 4 CKD who are taking a moderate to high dose of statin (≥40 mg/d of simvastatin or atorvastatin, or an equivalent dose of another statin) • A statin and fibrate should not be coadministered to patients with stage 4 CKD because of the risk of rhabdomyolysis Adapted from Levin A, et al: CMAJ 2008; 179(11):1154-62.

  46. Guidelines for the Management of CKD: Conclusions • The complexity of CKD clearly requires a better understanding of the absolute and relative value of identifying and treating the myriad clinical and laboratory abnormalities • It is critical that we better define the importance of these conditions for each stage of CKD • We must ensure that patients with CKD and any other risk factor for CVD receive aggressive treatment, and that a sense of therapeutic nihilism does not overcome our judgment and clinical care • The lack of evidence should encourage us to advocate for the design of and enrolment into randomized control trials that answer questions relevant to this population Levin A, et al: CMAJ 2008; 179(11):1154-62.

  47. GFR, Albuminuria and Risk of Cardiovascular and All-cause Mortality in the US Population Astor BC, et al: Am J Epidemiol 2008; 167(10):1226-34

  48. GFR, Albuminuria and the Risk of CV and All-cause Mortality in the US Population • Objective: To evaluate the separate and combined effects of decreased GFR and albuminuria on CV and all-cause mortality • Subjects:14,586 adults from NHANES III • Methodology: • GFR was estimated from standardized serum creatinine levels • Albuminuria was defined by the urinary albumin-creatinine ratio • Incidence rate ratios for mortality were adjusted for major CVD risk factors and C-reactive protein (CRP) Astor BC, et al: Am J Epidemiol 2008; 167(10):1226-34.

  49. GFR, Albuminuria and the Risk of CV and All-cause Mortality: Background • Patients with CKD are much more likely to die of CVD than to experience kidney failure • Experts have recommended using CKD in CV-risk stratification and treatment guidelines • Defining and staging kidney disease relies on combining information on kidney damage and decreased renal filtration • Most prospective studies examine one or the other, but not both • The risk associated with varying levels of albuminuria by level of kidney function has not been quantified in large cohort studies Adapted from Astor BC, et al: Am J Epidemiol 2008; 167(10):1226-34.

  50. GFR, Proteinuria and CV Risk • Lower GFR predicts CV events and mortality in: • Patients with existing CVD • Patients at high risk of CVD • The general population • Leakage of protein in the urine (proteinuria or albuminuria) is a sensitive indicator of: • Early kidney damage (especially in diabetes) • GFR decline • Higher risk of CVD and mortality Adapted from Astor BC, et al: Am J Epidemiol 2008; 167(10):1226-34.

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